Frequency of vaccine hesitancy among patients with advanced cancer.

BACKGROUND: Vaccine hesitancy has become prevalent in society. Vulnerable populations, such as those with cancer, are susceptible to increased morbidity and mortality from diseases that may have been prevented through vaccination. OBJECTIVES: Our objective was to determine patient perception of vaccine efficacy and safety and sources of information that influence decisions. METHODS: This study was a prospective cross-sectional survey trial conducted from March 10, 2022, to November 1, 2022, at a Supportive Care Clinic. Patients completed the survey with a research assistant or from a survey link. Vaccine hesitancy was defined as a response of 2 or more on the Parent Attitudes About Childhood Vaccines (PACV-4). Perception on vaccine safety and efficacy along with the importance of sources of information were determined by a questionnaire. RESULTS: Of the 72 patients who completed the PACV-4, 30 were considered vaccine-hesitant (42%). Of those who completed the survey alone (35), 23 (66%) were vaccine-hesitant; and of those who completed the survey with the help of a study coordinator (37), 7 (19%) were vaccine-hesitant. The most important source for decision-making was their doctor (82%, 95% CI 73-89), followed by family (42%, 95% CI 32-52), news/media (31%, 95% CI 22-41), and social media (9%, 95% CI 4-16). Clinical and demographic factors including age, gender, race/ethnicity, education level, and location of residence were not associated with vaccine hesitancy. SIGNIFICANCE OF RESULTS: Vaccine hesitancy is present among patients with advanced cancer. The high value given to the doctor's recommendation suggests that universal precautions regarding vaccine recommendation may be an effective intervention.

Opioid Prescription Denials by Community Pharmacies for Cancer-Related Pain: A Case Series.

Pain is one of the most common symptoms experienced by patients living with cancer. Guidelines recommend opioids as the mainstay in the management of cancer-related pain. However, the opioid epidemic has resulted in policymakers recommending limitations on opioid prescribing which led to community pharmacies implementing various parameters. These restrictions have created barriers for patients with cancer-related pain attempting to fill opioid prescriptions from their community pharmacies. Additionally, in the setting of the opioid epidemic, there have been reports of systemic bias within community pharmacies, leading to experiences with embarrassment and shame for patients with cancer-related pain. This case series presents specific examples of community pharmacies declining to fill opioid prescriptions for patients with cancer-related pain and associated patient suffering.

Quality of End-of-Life Care during the COVID-19 Pandemic at a Comprehensive Cancer Center.

To evaluate how the COVID-19 pandemic impacted the quality of end-of-life care for patients with advanced cancer, we compared a random sample of 250 inpatient deaths from 1 April 2019, to 31 July 2019, with 250 consecutive inpatient deaths from 1 April 2020, to 31 July 2020, at a comprehensive cancer center. Sociodemographic and clinical characteristics, the timing of palliative care referral, timing of do-not-resuscitate (DNR) orders, location of death, and pre-admission out-of-hospital DNR documentation were included. During the COVID-19 pandemic, DNR orders occurred earlier (2.9 vs. 1.7 days before death, p = 0.028), and palliative care referrals also occurred earlier (3.5 vs. 2.5 days before death, p = 0.041). During the pandemic, 36% of inpatient deaths occurred in the Intensive Care Unit (ICU) and 36% in the Palliative Care Unit, compared to 48 and 29%, respectively, before the pandemic (p = 0.001). Earlier DNR orders, earlier palliative care referrals, and fewer ICU deaths suggest an improvement in the quality of end-of-life care in response to the COVID-19 pandemic. These encouraging findings may have future implications for maintaining quality end-of-life care post-pandemic.

Patient Engagement With Early Stage Advance Care Planning at a Comprehensive Cancer Center.

BACKGROUND: Establishing care preferences and selecting a prepared medical decision-maker (MDM) are basic components of advance care planning (ACP) and integral to treatment planning. Systematic ACP in the cancer setting is uncommon. We evaluated a systematic social work (SW)-driven process for patient selection of a prepared MDM. METHODS: We used a pre/post design, centered on SW counseling incorporated into standard-of-care practice. New patients with gynecologic malignancies were eligible if they had an available family caregiver or an established Medical Power of Attorney (MPOA). Questionnaires were completed at baseline and 3 months to ascertain MPOA document (MPOAD) completion status (primary objective) and evaluate factors associated with MPOAD completion (secondary objectives). RESULTS: Three hundred and sixty patient/caregiver dyads consented to participate. One hundred and sixteen (32%) had MPOADs at baseline. Twenty (8%) of the remaining 244 dyads completed MPOADs by 3 months. Two hundred and thirty-six patients completed the values and goals survey at both baseline and follow-up: at follow-up, care preferences were stable in 127 patients (54%), changed toward more aggressive care in 60 (25%), and toward the focus on the quality of life in 49 (21%). Correlation between the patient's values and goals and their caregiver's/MPOA's perception was very weak at baseline, improving to moderate at follow-up. Patients with MPOADs by study completion had statistically significant higher ACP Engagement scores than those without. CONCLUSION: A systematic SW-driven intervention did not engage new patients with gynecologic cancers to select and prepare MDMs. Change in care preferences was common, with caregivers' knowledge of patients' treatment preferences moderate at best.

Inhalation of Isopropyl Alcohol for the Management of Nausea and Vomiting: A Systematic Review.

Background: The use of inhaled isopropyl alcohol (IPA) has been proposed as a therapeutic intervention for the relief of nausea in various settings. The objective of this systematic review was to evaluate the existing evidence for the use of inhaled IPA in the management of nausea and vomiting. Methods: We performed a literature search on Medline, EMBASE, Web of Science, Scopus, CINAHL, PsycInfo, and Cochrane Library databases before November 2021. The following concepts were searched using subject headings and keywords as needed "aromatherapy," "alcohol," "ethylic alcohol," "ethanol," "isopropyl alcohol," "emesis," "chemotherapy-induced," "pregnancy," "hyperemesis gravidarum," "motion sickness," "emetics," "antiemetics," "inhalation," and "inhale." Searches were not limited to a specific language. The bibliographies of identified articles were also manually searched. Two authors independently assessed the included studies for risk of bias. Results: Thirteen randomized controlled trials out of 158 studies identified met the inclusion criteria, with a total of 1253 participants. Twelve studies were conducted in the postoperative anesthesia care unit and two studies were performed in the emergency department setting. Four studies were double blinded, one was single blind, and eight were open label. Three studies assessed the use of inhaled IPA for prevention, whereas 10 studies evaluated its use in the treatment of nausea and vomiting. Seven studies reported IPA to be more effective, four studies reported no difference, and two studies reported IPA to be ineffective. Participant satisfaction was high overall, regardless of intervention received. No adverse effects were reported. The overall quality of evidence was low. Conclusion: There is a lack of strong evidence to support the use of inhaled IPA in the management of nausea and vomiting. Additional trials are warranted to confirm this finding and to further explore the use of inhaled IPA in various populations and settings.

Just-in-Time Decision Making: Preliminary Findings of a Goals of Care Rapid Response Team.

CONTEXT: The COVID-19 pandemic placed the issue of resource utilization front and center. Our comprehensive cancer center developed a Goals of Care Rapid Response Team (GOC RRT) to optimize resource utilization balanced with goal-concordant patient care. OBJECTIVES: Primary study objective was to evaluate feasibility of the GOC RRT by describing the frequency of consultations that occurred from those requested. Secondary objectives included adherence to consultation processes in terms of core team member participation and preliminary efficacy in limiting care escalation. METHODS: We conducted a retrospective chart review of patients referred to GOC RRT (3/23/2020-9/30/2020). Analysis was descriptive. Categorical variables were compared with Fisher's exact or Chi-Square tests and continuous variables with Mann-Whitney U tests. RESULTS: A total of 89 patients were referred. Eighty-five percent (76 of 89) underwent a total of 95 consultations. Median (range) patient age was 61 (49, 69) years, 54% (48 of 89) male, 19% (17 of 89) Hispanic, 48% (43/89) White, 73% (65 of 89) married/partnered and 66% (59 of 89) Christian. Hematologic malignancies and solid tumors were evenly balanced (53% [47/89] vs. 47% [42 of 89, P = 0.199]). Most patients (82%, 73 of 89) had metastatic disease or relapsed leukemia. Seven percent (6 of 89) had confirmed COVID-19. Sixty-nine percent (61 of 89) died during the index hospitalization. There was no statistically significant difference in demographic or clinical characteristics among groups (no consultation, 1 consultation, >1 consultation). Core team members were present at 64% (61 of 95) of consultations. Care limitation occurred in 74% (56 of 76) of patients. CONCLUSION: GOC RRT consultations were feasible and associated with care limitation. Adherence to core team participation was fair.

Timing of referral to outpatient palliative care for patients with haematologic malignancies.

Outpatient palliative-care facilitates timely supportive-care access; however, there is a paucity of studies on the timing of referral in the outpatient setting for patients with haematologic malignancy. We examined the trend in timing of outpatient palliative-care referrals over a 10-year period in patients with haematologic malignancies at our comprehensive cancer centre. We included consecutive patients with a diagnosis of haematologic malignancy who were seen at our outpatient palliative-care clinic between 1 January 2010 and 31 December 2019. We collected data on patient characteristics, symptom burden and supportive-care interventions at outpatient palliative-care consultation. The primary outcome was time from outpatient palliative-care consultation to death or last follow-up. In all, 384 patients were referred by leukaemia (n = 143), lymphoma (n = 213), and stem cell transplant (n = 28) services. The median time from outpatient palliative-care referral to death was 3.4 years (IQR 2.4-5.3) with a significant increase in both the number of referrals per year (p = 0.047) and the timing of referral between 2010 and 2019 (p = 0.001). Patients with haematologic malignancies were referred in a timely fashion to our outpatient palliative-care clinic, with earlier and greater numbers of referrals over time.

Timely Palliative Care: Personalizing the Process of Referral.

Timely palliative care is a systematic process to identify patients with high supportive care needs and to refer these individuals to specialist palliative care in a timely manner based on standardized referral criteria. It requires four components: (1) routine screening of supportive care needs at oncology clinics, (2) establishment of institution-specific consensual criteria for referral, (3) a system in place to trigger a referral when patients meet criteria, and (4) availability of outpatient palliative care resources to deliver personalized, timely patient-centered care aimed at improving patient and caregiver outcomes. In this review, we discuss the conceptual underpinnings, rationale, barriers and facilitators for timely palliative care referral. Timely palliative care provides a more rational use of the scarce palliative care resource and maximizes the impact on patients who are offered the intervention. Several sets of referral criteria have been proposed to date for outpatient palliative care referral. Studies examining the use of these referral criteria consistently found that timely palliative care can lead to a greater number of referrals and earlier palliative care access than routine referral. Implementation of timely palliative care at each institution requires oncology leadership support, adequate palliative care infrastructure, integration of electronic health record and customization of referral criteria.

Palliative care education and research at US cancer centers: A national survey.

BACKGROUND: Palliative care (PC) education and research are essential to developing a skilled workforce and evidence base to support the delivery of quality cancer care. The current state of PC education and research at US cancer centers is unclear. In this national survey, the education and research programs of the National Cancer Institute (NCI)-designated and nondesignated cancer centers and the changes between 2009 and 2018 are compared. METHODS: Between April and August 2018, PC program leaders at all NCI-designated cancer centers and a random sample of nondesignated centers were sent a survey to examine the structure, processes, and outcomes of their programs on the basis of questions from a 2009 national survey. This preplanned analysis focused on education and research. RESULTS: There were 52 of 61 (85%) NCI-designated and 27 of 38 (71%) nondesignated cancer centers that responded. NCI-designated centers were more likely than nondesignated centers to have a PC fellowship program (87% vs 30%; P < .001), training for advanced practice providers (71% vs 44%; P = .03), PC research program (58% vs 15%; P < .001), peer-reviewed funding (43% vs 11%; P = .005), and philanthropic grants (41% vs 7%; P = .002). There were few significant improvements in PC education or research between 2009 and 2018 for both groups, notable exceptions include an increase in PC fellowships (38% vs 87%; P < .001) and mandatory PC rotations for medical oncology fellows (29% vs 55%; P = .02) at NCI-designated cancer centers. CONCLUSIONS: PC education and research are more developed at NCI-designated cancer centers. Despite some progress over the past decade, it is relatively slow and suboptimal.

Frequency and Characteristics of First-Time Palliative Care Referrals During the Last Day of Life.

CONTEXT: Palliative care referrals (PCRs) improve symptom management, provide psychosocial and spiritual support, clarify goals of care, and facilitate discharge planning. However, very late PCR can result in increased clinician distress and prevent patients and families from benefiting from the full spectrum of interdisciplinary care. OBJECTIVES: To determine the frequency and predictors of PCR within 24 hours of death. METHODS: Consecutive first-time inpatient PCR from September 1, 2013 to August 31, 2017 was identified to determine the frequency and predictors of referrals within 24 hours of death. We compared the clinical characteristics with a random sample of patients discharged alive or died more than 24 hours after first-time PCR as a control, stratified by year of consult in a 1:1 ratio. RESULTS: Of 7322 first-time PCRs, 154 (2%) died within 24 hours of referral. These patients were older (P = 0.003) and had higher scores for depression (P = 0.0009), drowsiness (P = 0.02), and shortness of breath (P = 0.008) compared with a random sample of 153 patients discharged alive or died more than 24 hours after first-time PCR. Patients who received a PCR within 24 hours of death were more likely than the control group to have Eastern Cooperative Oncology Group 4 (95% vs. 25%, P < 0.0001), delirium (89% vs. 17%, P < 0.0001), do-not-resuscitate code status (81% vs. 18%, P < 0.0001), and hematologic malignancies (39% vs. 16%, P < 0.0001). In the multivariate analysis, depression (odds ratio [OR] 1.4; P = 0.005), do-not-resuscitate code status (OR 9.1; P = 0.003), and Eastern Cooperative Oncology Group 4 (OR 9.8; P = 0.003) were independently associated with first-time PCR within 24 hours of death. CONCLUSION: Although only a small proportion of first-time PCR occurred in the last 24 hours of life, the patients had a significant amount of distress, indicating a missed opportunity for timely palliative care intervention. These sentinel events call for specific guidelines to better support patients, families, and clinicians during this difficult time. Further research is needed to understand how to minimize very late PCR.

Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, randomised trial.

BACKGROUND: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium. METHODS: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1 mg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486. FINDINGS: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. INTERPRETATION: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group. FUNDING: National Institute of Nursing Research.

How to Use Methadone in an Era of an Opioid Epidemic.

OPINION STATEMENT: The opioid epidemic is one of the most important public health crises as opioid-related deaths have become a leading cause of accidental death in the USA. Various efforts have been made to understand how to safely and appropriately prescribe opioids for patients with chronic pain, including those with cancer-related pain. We find the guidelines proposed by the Expert Consensus White Paper on the use of methadone to be current, comprehensive, and practical. While methadone is a complex medication with unique pharmacokinetics and pharmacodynamics, it remains a superior choice for many patients with cancer pain given its cost and applicability in a variety of situations. Methadone should be prescribed in the context of experienced clinicians as well as an interdisciplinary team. At a critical time when preventing opioid-related deaths is a priority, we recommend implementing additional precautions for monitoring including universal screening for risk of non-medical opioid use, education on proper storage and disposal, as well as discussing a plan with patients and caregivers in the case of serious complications such as opioid overdose.

State of palliative care services at US cancer centers: An updated national survey.

BACKGROUND: This study examined the changes in outpatient palliative care services at US cancer centers over the past decade. METHODS: Between April and August 2018, all National Cancer Institute (NCI)-designated cancer centers and a random sample of 1252 non-NCI-designated cancer centers were surveyed. Two surveys used previously in a 2009 national study were sent to each institution: a 22-question cancer center executive survey regarding palliative care infrastructure and attitudes toward palliative care and an 82-question palliative care program leader survey regarding detailed palliative care structures and processes. Survey findings from 2018 were compared with 2009 data from 101 cancer center executives and 96 palliative care program leaders. RESULTS: The overall response rate was 69% (140 of 203) for the cancer center executive survey and 75% (123 of 164) for the palliative care program leader survey. Among NCI-designated cancer centers, a significant increase in outpatient palliative care clinics was observed between 2009 and 2018 (59% vs 95%; odds ratio, 12.3; 95% confidence interval, 3.2-48.2; P < .001) with no significant changes in inpatient consultation teams (92% vs 90%; P = .71), palliative care units (PCUs; 26% vs 40%; P = .17), or institution-operated hospices (31% vs 18%; P = .14). Among non-NCI-designated cancer centers, there was no significant increase in outpatient palliative care clinics (22% vs 40%; P = .07), inpatient consultation teams (56% vs 68%; P = .27), PCUs (20% vs 18%; P = .76), or institution-operated hospices (42% vs 23%; P = .05). The median interval from outpatient palliative care referral to death increased significantly, particularly for NCI-designated cancer centers (90 vs 180 days; P = 0.01). CONCLUSIONS: Despite significant growth in outpatient palliative care clinics, there remain opportunities for improvement in the structures and processes of palliative care programs.

Chronic Non-Malignant Pain in Patients with Cancer Seen at a Timely Outpatient Palliative Care Clinic.

Palliative care is seeing cancer patients earlier in the disease trajectory with a multitude of chronic issues. Chronic non-malignant pain (CNMP) in cancer patients is under-studied. In this prospective study, we examined the prevalence and management of CNMP in cancer patients seen at our supportive care clinic for consultation. We systematically characterized each pain type with the Brief Pain Inventory (BPI) and documented current treatments. The attending physician made the pain diagnoses according to the International Association for the Study of Pain (IASP) task force classification. Among 200 patients (mean age 60 years, 69% metastatic disease, 1-year survival of 77%), the median number of pain diagnosis was 2 (IQR 1-2); 67 (34%, 95% CI 28-41%) had a diagnosis of CNMP; 133 (67%) had cancer-related pain; and 52 (26%) had treatment-related pain. In total, 12/31 (39%) patients with only CNMP and 21/36 (58%) patients with CNMP and other pain diagnoses were on opioids. There was a total of 94 CNMP diagnoses among 67 patients, including 37 (39%) osteoarthritis and 20 (21%) lower back pain; 30 (32%) were treated with opioids. In summary, CNMP was common in the timely palliative care setting and many patients were on opioids. Our findings highlight the need to develop clinical guidelines for CNMP in cancer patients to standardize its management.

The Conversion Ratio From Intravenous Hydromorphone to Oral Opioids in Cancer Patients.

CONTEXT: The lack of knowledge of the accurate conversion ratio (CR) between intravenous (IV) and oral hydromorphone and opioid rotation ratio (ORR) between IV hydromorphone and oral morphine equivalent daily dose (MEDD) may lead to poorly controlled pain or overdosing in cancer inpatients. OBJECTIVES: We aimed to determine the CR and ORR from IV hydromorphone to oral hydromorphone and MEDD (obtained from oral morphine and oxycodone). METHODS: A total of 4745 consecutive inpatient palliative care consults during 2010-14 were reviewed for conversions from IV hydromorphone to oral hydromorphone, morphine or oxycodone. Patient characteristics, symptoms, and opioid doses were determined in patients successfully discharged on oral opioids without readmission within one week. Linear regression analysis was used to estimate the CR or ORR between the 24 hour IV hydromorphone mg dose before conversion and the oral opioid mg dose used before discharge. RESULTS: Among 394 patients on IV hydromorphone, 147 underwent conversion to oral hydromorphone and 247 underwent rotation to oral morphine (163) or oxycodone (84). The median (interquartile range) CR from IV to PO hydromorphone was 2.5 (2.14-2.75) with correlation of 0.95 (P < 0.0001). The median ORR (interquartile range) from IV hydromorphone to MEDD was 11.46 (9.84-13.00) with correlation of 0.93(P < 0.0001). The median ORR was 11.54 in patients receiving <30 mg of IV hydromorphone/day and 9.86 in patients receiving ≥30 mg (P = 0.0004). CONCLUSION: Our study found that 1 mg of IV hydromorphone is equivalent to 2.5 mg of oral hydromorphone and 11.46 mg of MEDD. Hydromorphone at doses ≥30 mg/day may require a lower ORR to other opioids.

The opioid rotation ratio of strong opioids to transdermal fentanyl in cancer patients.

BACKGROUND: Transdermal fentanyl (TDF) is 1 of the most common opioids prescribed to patients with cancer. However, the accurate opioid rotation ratio (ORR) from other opioids to TDF is unknown, and various currently used methods result in wide variation of the ORR. The objective of this study was to determine the ORR of the oral morphine equivalent daily dose (MEDD) to the TDF dose when correcting for the MEDD of breakthrough opioids (the net MEDD) in cancer outpatients. METHODS: The records of 6790 consecutive patients were reviewed at the authors' supportive care center from 2010 to 2013 to identify those who underwent rotation from other opioids to TDF. Data regarding Edmonton Symptom Assessment Scale scores and MEDDs were collected for patients who returned for a follow-up visit within 5 weeks. Linear regression analysis was used to estimate the ORR between the TDF dose and the net MEDD (the MEDD before opioid rotation [OR] minus the MEDD of the breakthrough opioid used along with TDF after OR). RESULTS: In total, 129 patients underwent OR from other opioids to TDF. The mean patient age was 56 years, 59% were men, and 88% had advanced cancer. Uncontrolled pain (80%) was the most frequent reason for OR. In 101 patients who underwent OR and had no worsening of pain at follow-up, the median ORR from net MEDD to TDF (in mg per day) was 0.01 (range, -0.02 to 0.04), and the correlation coefficient of the TDF dose to the net MEDD was 0.77 (P < .0001). The ORR was not significantly impacted by body mass index or serum albumin. The ORR of 0.01 suggests that an MEDD of 100 mg is equivalent to 1 mg TDF daily or approximately 40 micrograms per hour of TDF (1000 micrograms/24 hours). CONCLUSIONS: The median ORR from MEDD to TDF in mg per day was 0.01. These results warrant further studies.

Ribonucleotide reductase small subunit p53R2 facilitates p21 induction of G1 arrest under UV irradiation.

p53R2, which is one of the two known ribonucleotide reductase small subunits (the other being M2), is suggested to play an important role in supplying deoxynucleotide triphosphates (dNTP) for DNA repair during the G(1) or G(2) phase of the cell cycle. The ability of p53R2 to supply dNTPs for repairing DNA damages requires the presence of a functional p53 tumor suppressor. Here, we report in vivo physical interaction and colocalization of p53R2 and p21 before DNA damage. Mammalian two-hybrid assay further indicates that the amino acids 1 to 113 of p53R2 are critical for interacting with the NH(2)-terminal region (amino acids 1-93) of p21. The binding between p21 and p53R2 decreases inside the nucleus in response to UV, the time point of which corresponds to the increased binding of p21 with cyclin-dependent kinase-2 (Cdk2), and the decreased Cdk2 activity in the nucleus at G(1). Interestingly, p53R2 dissociates from p21 but facilitates the accumulation of p21 in the nucleus in response to UV. On the other hand, the ribonucleotide reductase activity increases at the corresponding time in response to UV. These data suggest a new function of p53R2 of cooperating with p21 during DNA repair at G(1) arrest.

Structurally dependent redox property of ribonucleotide reductase subunit p53R2.

p53R2 is a newly identified small subunit of ribonucleotide reductase (RR) and plays a key role in supplying precursors for DNA repair in a p53-dependent manner. Currently, we are studying the redox property, structure, and function of p53R2. In cell-free systems, p53R2 did not oxidize a reactive oxygen species (ROS) indicator carboxy-H2DCFDA, but another class I RR small subunit, hRRM2, did. Further studies showed that purified recombinant p53R2 protein has catalase activity, which breaks down H2O2. Overexpression of p53R2 reduced intracellular ROS and protected the mitochondrial membrane potential against oxidative stress, whereas overexpression of hRRM2 did not and resulted in a collapse of mitochondrial membrane potential. In a site-directed mutagenesis study, antioxidant activity was abrogated in p53R2 mutants Y331F, Y285F, Y49F, and Y241H, but not Y164F or Y164C. The fluorescence intensity in mutants oxidizing carboxy-H2DCFDA, in order from highest to lowest, was Y331F > Y285F > Y49F > Y241H > wild-type p53R2. This indicates that Y331, Y285, Y49, and Y241 in p53R2 are critical residues involved in scavenging ROS. Of interest, the ability to oxidize carboxy-H2DCFDA indicated by fluorescence intensity was negatively correlated with RR activity from wild-type p53R2, mutants Y331F, Y285F, and Y49F. Our findings suggest that p53R2 may play a key role in defending oxidative stress by scavenging ROS, and this antioxidant property is also important for its fundamental enzymatic activity.